College of Pharmacy, The University of Tennessee, Memphis, TN, USA.
Mol Cancer. 2011 Nov 10;10:138. doi: 10.1186/1476-4598-10-138.
Pancreas cancer is one of most aggressive human cancers with the survival rate for patients with metastatic pancreas cancer at 5-6 months. The poor survival demonstrates a clear need for better target identification, drug development and new therapeutic strategies. Recent discoveries have shown that the role for Notch pathway is important in both development and cancer. Its contribution to oncogenesis also involves crosstalks with other growth factor pathways, such as Akt and its modulator, PTEN. The mounting evidence supporting a role for Notch in cancer promotion and survival suggests that targeting this pathway alone or in combination with other therapeutics represents a promising therapeutic strategy.
Using a pancreas cancer tissue microarray, we noted that Jagged1, Notch3 and Notch4 are overexpressed in pancreas tumors (26%, 84% and 31% respectively), whereas Notch1 is expressed in blood vessels. While there was no correlation between Notch receptor expression and survival, stage or tumor grade, Notch3 was associated with Jagged1 and EGFR expression, suggesting a unique relationship between Notch3 and Jagged1. Inhibition of the Notch pathway genetically and with gamma-secretase inhibitor (GSI) resulted in tumor suppression and enhanced cell death. The observed anti-tumor activity appeared to be through Akt and modulation of PTEN phosphorylation. We discovered that transcriptional regulation of RhoA by Notch is important for PTEN phosphorylation. Finally, the mTOR inhibitor Rapamycin enhanced the effect of GSI on RhoA expression, resulting in down regulation of phospho-Akt and increased in vitro tumor cytotoxity.
Notch pathway plays an important role in maintaining pancreas tumor phenotype. Targeting this pathway represents a reasonable strategy for the treatment of pancreas cancers. Notch modulates the Akt pathway through regulation of PTEN phosphorylation, an observation that has not been made previously. Furthermore, we discovered that this regulation is dependent on RhoA/Rock1 activation. Enhanced phospho-Akt suppression when GSI is combined with rapamycin suggests that targeting both pathways will lead to a greater efficacy in the treatment of patients with pancreas cancer.
胰腺癌是最具侵袭性的人类癌症之一，转移性胰腺癌患者的生存率为 5-6 个月。这种较差的生存率表明，非常需要更好的靶点鉴定、药物开发和新的治疗策略。最近的发现表明，Notch 通路在发育和癌症中都具有重要作用。它对肿瘤发生的贡献还涉及与其他生长因子通路（如 Akt 及其调节剂 PTEN）的交叉对话。越来越多的证据支持 Notch 在癌症促进和存活中的作用表明，单独靶向该通路或与其他治疗方法联合使用代表了一种很有前途的治疗策略。
使用胰腺癌组织微阵列，我们注意到 Jagged1、Notch3 和 Notch4 在胰腺肿瘤中过度表达（分别为 26%、84%和 31%），而 Notch1 在血管中表达。虽然 Notch 受体表达与生存率、分期或肿瘤分级之间没有相关性，但 Notch3 与 Jagged1 和 EGFR 表达相关，表明 Notch3 与 Jagged1 之间存在独特的关系。遗传抑制 Notch 通路和使用γ-分泌酶抑制剂（GSI）可导致肿瘤抑制和增强细胞死亡。观察到的抗肿瘤活性似乎是通过 Akt 调节和 PTEN 磷酸化。我们发现，Notch 对 RhoA 的转录调控对 PTEN 磷酸化很重要。最后，mTOR 抑制剂雷帕霉素增强了 GSI 对 RhoA 表达的影响，导致磷酸化 Akt 的下调和体外肿瘤细胞毒性的增加。
Notch 通路在维持胰腺肿瘤表型方面发挥着重要作用。靶向该通路是治疗胰腺癌的合理策略。Notch 通过调节 PTEN 磷酸化来调节 Akt 通路，这是以前没有观察到的。此外，我们发现这种调节依赖于 RhoA/Rock1 的激活。当 GSI 与雷帕霉素联合使用时，增强磷酸化 Akt 的抑制作用表明，靶向两条通路将导致治疗胰腺癌患者的疗效更大。
